Geum Japonicun Thunb ver. is a plant generally growing in Jiangsu province, Jiangxi province, Guizhou province and Yunan province, China. Geum is a genus of 65 species of rhizomatous herbs and subshrubs with simple or pinnately lobed leaves and regular flowers such as G. borisii, G. chiloense, G. coccineum, G. macrophyllum, G. montanum, G. reptans, G. rivale, G. triflorum, G. urbanum and G. japonicum etc. Geum japonicum Thunb. is a perennial herb and the flowering plant of the Rosaceae family. Water extract of the whole plant of Geum japonicum Thunb has been used as a diuretic in traditional Chinese medicine, Perry, L. M., in Medicinal Plants of East and Southeast Asia, MIT Press, Cambridge, Mass., pp. 343 (1980). The plants of Geum species has been known to be rich in tannins. Several hydrolyzable tannins, such as gemin A, B, C, D, E and F, have been isolated from Geum japonicum, Dong, H., Chen, S. X., Kini, R. M., and Xu, H. X., J. Nat. Products. 61, 1356-60 (1998). In addition to tannins, some triterpenoids including 2-hydroxyoleanolic acid, 2-hydroxyursolic acid, 2,19-dihydroxy-ursolic acid, 2,3,19,23-tetrahydroxyurs-12-en-28-oic acid 28-O-D-glucopyranoside were isolated, Xu, H. X., Zeng, F. Q., Wan, M., and Sim, K. Y., J. Nat. Products, 59, 643-5 (1996).
However, no information has been disclosed on the use of an EGJ in treating ischemic diseases and damaged myocardium. Ischemic diseases, such as coronary heart disease remains the leading cause of death in the Western world, such as in America and in developed regions in Asia, such as in Hong Kong, and now becoming so in China as well, American Heart Association, 2001 Heart and Stroke Statistical Update, Dallas, Tex.: American Heart Association, 2000, 1-32. Currently, available therapeutic approaches thereto can only relieve symptoms and unfortunately, even with all the recent advances, cure of these kinds of ischemic diseases and damaged myocardium is difficult due to the lack of a method to grow functional new vessels at early stage in ischemic myocardium and the inability to regenerate cardiomyocytes, Uchida, Y., Yanagisawa-Miwa, A., Nakamura, F., Yamada, K., Tomaru, T., Kimura, K., and Morita, T., Am Heart J. 130: 1182-1188 (1995); Lazarous, D. F., Scheinowitz, M., Shou, M., Epstein, S. E., and et al, Circulation 91: 145-153 (1995); Pu, L. Q., Sniderman, A. D., Brassard, R., Lachapelle, K. J., Graham, A. M., Lisbona, R., and symes, J. F., Circulation 88: 208-215 (1993). According to previous studies in both acute and chronic ischemic animal models or clinical trials, angiogenesis by using growth factors, such as VEGF, aFGF, bFGF or PDGF requires time (on the order of 3-9 weeks) and is limited, (8-15) Risau, W., Nature 386: 671-674 (1997); Folkman, J., N. Engl. J. Med. 333: 1757-1763 (1995); Ware. J. A., Anigiogeniesis and Cardiovascular Disease (J. A. Ware and M. Simons, eds), Oxford University Press, New York, Oxford, 30-59 (1999); Ware, J. A., and Simons, M., Nat. Med. 3: 158-164 (1997); Arras, M., Ito, W. D., Scholz, D., Winkler, B., Schaper, J., and Schaper, W., J. Clin. Invest. 101: 40-50 (1998); Banai, S., Jaklitsch, M. T., Casscells, W., Shou, M., Shrivastav, S., Correa, R., Epstein, S. E. and Unger, E. F., Circ. Res. 69, 76-85 (1991); Arras, M., Mollnau, H., Strasser, R., Ito, W. D., Schaper, J., and Schaper, W., Nat. Biotechnol. 16: 159-162 (1998); Kurz, H., Wilting, J., Sandau, K., and Christ, B., Microvasc. Res. 55: 92-102 (1998), while myocardium necrosis due to coronary occlusion occurs very rapidly (hours), Unger, E. F., Shou, M., Sheffield, C. D., Hodge, E., Jaye, M., & Epstein, S. E., Am. J. Phlysiol. 264: H1567-1574 (1993); Unger, E. F., Banai, S., Shou, M., Jaklitsch, M., Hodge, E., Correa, R., Jaye, M., & Epstein, S. E., Cardiovasc. Res. 27: 785-791 (1993); and Schlaudraff, K., Schumacher, B., von Specht, B. U., Seitelberger, R., Schlosser, V., & Fasol, R., Eur. J. Cardiothorac. Surg. 7: 637-643 (1993). Therefore, therapeutic early angiogenesis and cardiomyogenesis may provide the most useful alternative strategy, which, if successful, may become the major therapeutic option in many ischemic diseases and damaged myocardium.
Up to now, there is no similar product available in the world market that is capable of inducing early angiogenesis in the heart and regeneration of myocardium is completely novel. According to previous studies in both acute and chronic ischemic animal models or clinical trials, some growth factors, such as VEGF, aFGF, bFGF or PDGF could enhance angiogenesis in certain degree, but it takes time (on the order of weeks) while myocardial necrosis due to coronary occlusion occurs very rapidly (in a mater of hours). Therefore, inducing early angiogenesis has become an important goal in reducing the size of infarction in the heart and rescuing affected tissue. Furthermore, even with all most recent advances in sciences and in research fields, there is no method or any drugs that could be used to regenerate cardiac myocytes.
In our recent studies, we have identified an extract of a Chinese herbal medicine-geum Japonicum thunb var that showed potent effects on stimulating early growth of new vessels (<48 h) and regeneration of cardiomyocytes in rabbit acute myocardium infraction model. In comparison to the period of weeks of naturally occurring angiogenesis and angiogenesis by using growth factors, EGJ induced angiogenesis in myocardium takes less than 48 hours. This unique feature of early angiogenesis induced by EGJ is therefore very useful in developing a new strategy for effective treatment of ischemic diseases, especially important in reduction of infarction size, rescuing affected cardiac myocytes while heart infarction occurs as demonstrated in our animal experiments.
The concept of therapeutic angiogenesis by augmenting the naturally occurring revascularizing process for the treatment of ischemic vascular diseases is a very attractive idea. It provides us with the opportunity to achieve more complete revascularization in patients with ischemic related diseases, such as coronary heart disease or heart infarction. For ischemic heart disease, apart from prevention, at present, blockages in the coronary arteries can only be relieved by surgery or angioplasty. There is no effective medicine that can stimulate the growth of new blood vessels (angiogenesis) at early stage. Furthermore, after myocardial infarction, the myocardium is incapable of regenerating new cardiomyocytes to replace the lost muscle cells. Scar tissues, which replace the necrosed myocardium, further, cause deterioration in cardiac function. Therefore, it is clear that an alternative revascularization strategy is required to treat ischaemia and stimulate replacement of damaged or lost heart muscle cells. Therapeutic angiogenesis and cardiomyogenesis would be the most useful alternative strategy, which may become the main therapeutic option in the treatment of many ischemic diseases including coronary heart diseases and ischemic limbs, and damaged myocardium. It may even be able to replace some of the current therapeutic modalities with a less invasive strategy, yet much more effective if early angiogenesis can be achieved.
The invention is to fulfill the purpose of growing new vessels at early stage and regenerating cardiac myocytes in infarcted myocardium to replace the damaged myocardium with the use of EGJ. EGJ can be applied by local myocardium injection directly to the distal parts of an occluded vessel in ischemic heart, or limbs. It can also be potentially developed into an oral administration (pills) or injection to blood stream or muscles in the patients who are unbearable to local myocardium injection and proved with no neoplasm formation or tumors.
The current invention relates to an organic extract, particularly a methanol extract of Geum Japonicum thunb var. that stimulates early angiogenesis and myocardial regeneration in ischemic heart and myocardial infarction and therefore is useful in treating ischemic diseases, such as ischemic heart disease including coronary heart disease, heart infarction, ischemic limbs, damaged myocardium and tissue healing.